Platinum Based Chemotherapy or Capecitabine in Treating Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy
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| ClinicalTrials.gov Identifier: NCT02445391 |
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Recruitment Status :
Recruiting
First Posted : May 15, 2015
Last Update Posted : October 12, 2018
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Estrogen Receptor Negative HER2/Neu Negative Invasive Breast Carcinoma Progesterone Receptor Negative Stage II Breast Cancer Stage IIA Breast Cancer Stage IIB Breast Cancer Stage III Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Triple-Negative Breast Carcinoma | Drug: Capecitabine Drug: Carboplatin Drug: Cisplatin Other: Laboratory Biomarker Analysis Procedure: Quality-of-Life Assessment Other: Questionnaire Administration | Phase 3 |
PRIMARY OBJECTIVES:
I. To compare the invasive disease-free survival (IDFS) in triple-negative breast cancer (TNBC) patients with residual basal-like disease after neoadjuvant chemotherapy who are randomized to post-preoperative platinum based chemotherapy with those who are randomized to capecitabine.
SECONDARY OBJECTIVES:
I. To evaluate overall survival (OS) and response-free survival (RFS) in the two arms in patients with TNBC with residual basal-like disease after neoadjuvant chemotherapy.
II. To characterize the side effects and tolerability of each platinum agent (cisplatin and carboplatin) as well as capecitabine in patients with TNBC with residual disease after neoadjuvant chemotherapy.
III. To identify the rate of basal-like gene expression using prediction analysis of microarray 50 (PAM50) analysis by digital messenger ribonucleic acid (mRNA) quantitation amongst drug-resistant residual TNBC after neoadjuvant chemotherapy.
IV. To compare the IDFS in TNBC patients with residual non-basal-like disease after neoadjuvant chemotherapy who are randomized to post-preoperative platinum based chemotherapy with those who are randomized to capecitabine (exploratory analysis).
V. To assess the difference in health-related quality of life (HRQL) between the platinum based and capecitabine chemotherapy arms.
VI. To describe the rate of neurotoxicity over time in the platinum arm, the rate of medication adherence in the capecitabine arm and the rates of amenorrhea in both arms (exploratory).
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM A (closed to accrual 05/16/2016): Patients undergo observation.
ARM B: Patients receive cisplatin intravenously (IV) or carboplatin IV on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
ARM C: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for up to 10 years.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 562 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized Phase III Post-operative Trial of Platinum Based Chemotherapy vs. Capecitabine in Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy |
| Actual Study Start Date : | April 29, 2015 |
| Estimated Primary Completion Date : | May 31, 2019 |
| Estimated Study Completion Date : | May 31, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Arm A (observation) (closed to accrual 05/16/2016)
Patients undergo observation.
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Other: Laboratory Biomarker Analysis
Correlative studies Procedure: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
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Experimental: Arm B (cisplatin or carboplatin)
Patients receive cisplatin IV or carboplatin IV on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
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Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
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Experimental: Arm C (capecitabine)
Patients receive capecitabine PO BID on days 1-14. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
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Drug: Capecitabine
Given PO
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
- Invasive disease-free survival (IDFS) of patients with basal-like triple-negative breast cancer (TNBC) [ Time Frame: From randomization to the earliest of documented disease recurrence (local, regional and/or distant), invasive contralateral breast cancer, invasive any other second primary cancer, or death, assessed up to 86 months after study activation ]The distributions of IDFS will be estimated using the Kaplan- Meier method. For the non-inferiority test, the primary analysis of IDFS comparisons will be performed using the repeated confidence interval (RCI) method with hazard ratio (HR) being estimated via stratified Cox proportional hazard model, stratifying on the randomization stratification factors. For the superiority tests of IDFS, the primary analysis will be performed using stratified log-rank tests, and stratified Cox proportional-hazard models will also be built to estimate the HRs for treatment effect for this efficacy endpoint a
- Incidence of toxicity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 86 months after study activation ]All treatment-emergent and baseline adverse events and hematological/biochemical toxicities based on laboratory measurements will be summarized for patients on platinum agent. The incidence of deaths and treatment-emergent serious adverse events will be calculated along with exact 95% confidence interval (CI) based on binomial distribution. Also, the incidence of adverse events leading to discontinuation of chemotherapy and/or withdrawal from the study will be summarized and listed as well.
- Overall survival (OS) of patients with basal-like triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy [ Time Frame: Time from randomization to death from any cause, assessed up to 116 months after study activation ]The distributions of OS will be estimated using the Kaplan- Meier method. For the superiority tests of OS, the primary analysis will be performed using stratified log-rank tests, and stratified Cox proportional-hazard models the will also be built to estimate the HRs for treatment effect for this efficacy endpoint as a supportive analysis
- Patient reported outcome (PRO) [ Time Frame: Up to 15 months ]Standard descriptive and graphical analyses will be used initially to examine missing data patterns, and to understand the relationship between variables for health-related quality of life (HRQL) scores. The assessment scores for the HRQL will be compared between the two treatment arms at all time points, using two samples t test (or Wilcoxon rank sum test58 if the distribution of the score is not symmetric). Change in the HRQL scores between all other timepoints and the baseline visits will be compared between the two arms using two sample t tests. The mean score and proportion of moderate/se
- Rate of basal-like gene expression using PAM50 analysis by digital mRNA quantification [ Time Frame: Baseline ]The proportion of basal-like TNBC in all screened TNBC patients will be calculated with exact 95% CI based on binomial distribution.
- Recurrence-free survival (RFS) [ Time Frame: Up to 86 months after study activation ]The distributions of RFS will be estimated using the Kaplan- Meier method. For the superiority tests of RFS, the primary analysis will be performed using stratified log-rank tests, and stratified Cox proportional-hazard models the will also be built to estimate the HRs for treatment effect for this efficacy endpoint as a supportive analysis.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- ELIGIBILITY CRITERIA FOR SCREENING AND MOLECULAR PROFILING (STEP 0)
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 2 weeks prior to screening
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Female and male patients must have histologically confirmed invasive breast cancer that meets the following criteria:
- Clinical stage II-III (American Joint Committee on Cancer [AJCC] 7th edition) at diagnosis, based on initial evaluation by clinical examination and/or breast imaging; no metastatic disease allowed
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ER- and PR- should meet one of the following criteria:
- =< 10% cells stain positive, with weak intensity score (equivalent to Allred score =< 3)
- =< 1% cells stain positive, with weak or intermediate intensity score (equivalent to Allred score =< 3)
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HER2 negative (not eligible for anti-HER2 therapy) will be defined as:
- Immunohistochemistry (IHC) 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR
- IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells OR
- ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells without IHC
- NOTE: Patients that originally present with synchronous bilateral tumors are eligible provided both tumors are TNBC, and at least one of them fulfills the remainder eligibility criteria of the protocol; multifocal or multicentric breast cancers are eligible as long as all tumors fulfill eligibility criteria
- NOTE: Patients that have a discrepancy in ER/PR/HER2 status between original diagnosis and surgical specimen (if ER/PR/HER2 status were repeated) are not eligible for study participation (i.e. ER/PR/HER2 has to fulfill above criteria in both scenarios)
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Patients must have completed neoadjuvant taxane +/- anthracycline; patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen
- NOTE: Patients who received preoperative therapy as part of a clinical trial may enroll
- NOTE: Patients that were not able to complete their planned neoadjuvant chemotherapy for any reason (i.e. toxicities, etc.) are eligible to participate as long as no further systemic standard of care therapy is planned by the treating physician
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Must have completed definitive resection of primary tumor
- Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible
- Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable
- Sentinel node biopsy either pre or post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) are allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory
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Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer in the breast at the time of definitive surgery; residual cancer is defined as a contiguous focus of residual invasive cancer, in the breast, measuring >= 1 cm in diameter, and with more than minimal cellularity, as per local pathologist determination; this is required due to constraints in deoxyribonucleic acid (DNA) extraction for PAM50 analysis
- NOTE: The presence of ductal carcinoma in situ (DCIS) without invasion does not qualify as residual invasive disease in the breast
- NOTE: Despite lymph node involvement if residual invasive cancer in the breast is < 1 cm in diameter patients are not eligible for participation
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Radiotherapy may be given before or after protocol treatment per standard of care guidelines; when radiotherapy is planned prior to protocol treatment administration, patients may be registered and screened while receiving radiation
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Post-mastectomy radiotherapy is required for all patients with the following:
- Primary tumor >= 5 cm (prior to neoadjuvant chemotherapy [clinically] or at the time of definitive surgery) or involvement of 4 or more lymph nodes at the time of definitive surgery
- For patients with primary tumors < 5 cm or with < 4 involved lymph nodes prior to neoadjuvant chemotherapy and at the time of definitive surgery, provision of post-mastectomy radiotherapy is at the discretion of the treating physician
- Radiation of regional nodal basins is at the discretion of the treating radiation oncologist
- NOTE: Breast radiotherapy (whole breast or partial) is required for patients who underwent breast-conserving therapy, including lumpectomy or partial mastectomy
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- Hemoglobin (Hgb) > 9.0 g/dL
- Platelets > 100,000 mm^3
- Absolute neutrophil count (ANC) > 1500 mm^3
- Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula
- Bilirubin =< 1.5 x ULN upper limit of normal (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL)
- Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x upper limit of normal (ULN)
- Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
- No history of TNBC invasive breast cancer within 5 years of enrollment, no concurrent malignancies of any sort
- No clinically significant infections as judged by the treating investigator
- Patients with active >= Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 grade 2 neuropathy are ineligible
- Adjuvant chemotherapy after surgery other than that specified in this protocol is not allowed; luteinizing hormone-releasing hormone (LHRH) agonists and adjuvant bisphosphonate or denosumab use is allowed
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Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the residual disease on the definitive surgical specimen available for PAM50 analysis for stratification
- Tumor tissue specimen from the definitive surgery has been collected and is ready to ship to the ECOG-American College of Radiology Imaging Network (ACRIN) Central Biorepository and Pathology Facility (CBPF) within 21 weeks post-surgery
- The Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer Center will perform the PAM50 analysis and notify the ECOG-American College of Radiology Imaging Network (ACRIN) operations office within three (3) weeks of receipt of the tumor tissue specimen via secure electronic messaging to the ECOG-ACRIN database; results will not be reported to the submitting institution
- NOTE: Tissue must be submitted any time during screening period, even if patient is getting radiation
- NOTE: Every effort should be made to submit the tumor tissue specimen to the ECOG-ACRIN CBPF immediately
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ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): No specific timeframe between registration and randomization needs to be observed, as long as:
- Patients randomized to the chemotherapy arms have their cycle 1/ day 1 (platinum based or capecitabine) start within 3 weeks (15 working days) following randomization date
- Randomization occurs no more than 24 weeks from surgery date
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Must have PAM50 analysis by digital mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast or axilla resected at the time of definitive surgery completed
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): ECOG performance status 0 or 1 within 2 weeks prior to randomization
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Radiotherapy may be given before or after protocol treatment. when radiotherapy is planned prior to protocol treatment administration, patients must have completed adjuvant radiotherapy >= 2 weeks prior to randomization for protocol therapy, if applicable
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must have completed treatment with any investigational agent >= 30 days prior to randomization for protocol therapy, if applicable
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must be randomized within 24 weeks from surgery
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ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy
- A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Hemoglobin (Hgb) > 9.0 g/dL
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Platelets > 100,000 mm^3
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Absolute neutrophil count (ANC) > 1500 mm^3
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): International normalized ratio (INR) =< 3 (to be done/tested only for subjects on warfarin)
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Bilirubin =< 1.5 x ULN (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL)
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Aspartate aminotransferase (AST, SGOT) =< 2.5 x ULN
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Alanine aminotransferase (ALT, SGPT) =< 2.5 x ULN
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02445391
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| Principal Investigator: | Ingrid Mayer | ECOG-ACRIN Cancer Research Group |
| Responsible Party: | ECOG-ACRIN Cancer Research Group |
| ClinicalTrials.gov Identifier: | NCT02445391 History of Changes |
| Other Study ID Numbers: |
EA1131 NCI-2014-01820 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) EA1131 EA1131 ( Other Identifier: ECOG-ACRIN Cancer Research Group ) EA1131 ( Other Identifier: CTEP ) U10CA180820 ( U.S. NIH Grant/Contract ) U24CA196172 ( U.S. NIH Grant/Contract ) |
| First Posted: | May 15, 2015 Key Record Dates |
| Last Update Posted: | October 12, 2018 |
| Last Verified: | October 2018 |
Additional relevant MeSH terms:
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Carcinoma Breast Neoplasms Triple Negative Breast Neoplasms Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Neoplasms by Site Breast Diseases |
Skin Diseases Cisplatin Carboplatin Capecitabine Antineoplastic Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action |